U.S. Pat. No. 4,921,982 describes a series of bicyclic carboxylic esters and amides which are reported to be specific 5HT.sub.3 antagonists. Many of the preferred compounds in this reference have a bicyclic nucleus of the 2,2-dimethyl-2,3-benzofuran-7-carboxylic acid type. See, e.g., Formula Ia and appropriate intermediates of Formula IIa.
The process for preparing the carboxylic acid intermediates required for the synthesis of the esters and amides provided by this patent is disclosed in Scheme 2 of this reference. In the case of the oxygen-containing bicyclic system, a minimum of 5 steps is required to convert the phenol-ester of Formula IV to the corresponding bicyclic carboxylic acid of Formula II. The protection and deprotection of the acid functionality are two steps required by this scheme which can adversely affect yield and otherwise add to the overall economy of preparing such intermediates.
Similar chemistry is also reported for related compounds; see, e.g., Reaction Schemes I and II in each of EPO Patent Application Publications 147044 and 234872.
It has now been discovered that many of the preferred intermediates reported in U.S. Pat. No. 4,921,982 can be prepared in a 3-step sequence from ortho-hydroxy benzoic acids in high yield.